Untargeted red blood cell metabolomics reveals distinct metabolic signatures in malignant cerebral edema following acute ischemic stroke

Background:

Malignant cerebral edema (MCE) is a major cause of mortality and disability in acute ischemic stroke, yet effective treatments remain limited. Identifying specific biomarkers for early prediction and therapeutic guidance of MCE is an ongoing clinical challenge.

Methods:

Patients with large vessel occlusion were prospectively enrolled and classified into MCE and non-MCE groups based on the Thrombolysis in Stroke-Monitoring Study criteria. Plasma, red blood cells (RBCs), and urine samples were collected on days 1, 3, and 7 post - onset for preliminary analysis to determine the optimal biofluid and time point. Untargeted metabolomics using ultra-performance liquid chromatography–tandem mass spectrometry was then performed on expanded samples.

Results:

Exploratory screening (n=3 per group) revealed that day 1 RBC samples exhibited the highest number of differential metabolites. Consequently, day 1 RBCs from 61 patients (19 MCE, 42 non-MCE) were analyzed. Baseline characteristics were balanced between groups. A total of 521 differential metabolites were identified, with 177 upregulated and 344 downregulated in the MCE group. Notable altered metabolites included palmitoylethanolamide, S-adenosylmethionine, and spermidine. These were primarily enriched in pathways related to cofactor biosynthesis, neuroactive ligand-receptor interactions, and amino acid metabolism.

Conclusion:

This study presents the first untargeted metabolomic profiling of RBCs in large vessel occlusion - acute ischemic stroke patients, revealing key metabolites and pathways associated with MCE. These findings provide novel insights into MCE pathophysiology and offer promising candidates for early biomarkers and potential therapeutic targets.

Dr. Zhang Baizhi is a neurology master's graduate student specializing in the pathophysiological mechanisms of post-stroke cerebral edema. She has authored multiple research papers, including one SCI-indexed paper as the first author.